Many Iraq and Afghanistan Veterans have experienced repetitive blast exposure mild traumatic brain injury (mTBI) with persistent cognitive, emotional, and neurological postconcussive symptoms. Our own neuroimaging and cerebrospinal fluid (CSF) biomarker studies demonstrate consistent evidence of diffuse axonal injury and functional deficits on neuroimaging and preliminary CSF biomarker evidence of incipient tauopathy. There is an urgent need to develop effective treatments to reduce both the intensity of these Veterans' current symptoms as well as their potential long-term risks for developing neurodegenerative dementing disorders related to repetitive mTBI: chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Converging evidence from: 1) studies of neuroprotective effects of statins in animal models of TBI; 2) our epidemiological studies of statin effects on clinical and neuropathological manifestations of AD; and 3) our 14 week pilot study of simvastatin vs. pravastatin effects on CSF AD biomarkers in middle-aged, non- demented subjects suggest that statins may possess neuroprotective effects against pathologic processes related to tau protein metabolism that appear to be a common feature of CTE, AD, and other neurodegenerative sequelae of repetitive mTBI. In addition, our extensive CSF biomarker studies in AD patients and normal controls, our past and current pilot clinical trials of simvastatin in cognitively normal subjects, and our neuroimaging and CSF biomarker studies in Iraq and Afghanistan Veterans together demonstrate the feasibility of using CSF biomarkers of neurodegenerative processes (such as total (t)-tau and phosphorylated (p)-tau181) and neurogenesis (brain derived neurotrophic factor) as viable and reliable outcome measures in trials of putative preventive treatments in Iraq and Afghanistan subjects at risk of developing neurodegenerative dementing disorders due to repetitive blast-exposure mTBI. We propose a 12-month, double-blind, randomized, placebo-controlled trial to establish proof-of- concept for use of simvastatin (40 mg/d) for decreasing CSF biomarkers of neurodegeneration and increasing CSF neurotrophins in 120 Iraq and Afghanistan Veterans with repetitive blast trauma mTBI. Specific Aims are: Specific Aim 1: To examine the effects of 12 months of treatment with simvastatin 40 mg/day on CSF concentrations of tau biomarkers (t-tau, p-tau181, and t-tau:p-tau181 ratio) and brain-derived neurotrophic factor (BDNF) in Iraq and Afghanistan Veterans with repetitive blast concussion mTBI. Hypothesis 1: Compared to placebo, simvastatin will reduce levels of CSF t-tau, p-tau181, and p-tau181:t- tau ratio; and will increase level of CSF BDNF. Specific Aim 2: To explore the effects of 12 months of treatment with simvastatin 40mg/day on CSF A42, and biomarkers of oxidative stress and neuroinflammation in Iraq and Afghanistan Veterans with repetitive blast concussion mTBI. Hypothesis 2: Compared to placebo, simvastatin will reduce levels of CSF A42, and biomarkers of oxidative stress (F2-isoprostanes) and neuroinflammation (interleukin-6 [IL-6], IL-8, and S100). Because of concerns regarding potential adverse effects of statins, we will also administer a neurocognitive test battery to monitor memory and other cognitive functions during the study period. We will also monitor potential effects of simvastatin treatment on persistent postconcussive symptoms (PPCS), posttraumatic stress disorder (PTSD), depression, alcohol use, functional status, and health-related quality of life. The findings of the proposed study may provide, in a relatively short period of time, proof-of- concept in support of larger scale primary prevention trials to prevent neurodegeneration and dementia in Iraq and Afghanistan Veterans and service members with repetitive mTBI. PUBLIC HEALTH RELEVANCE: Because improvised explosive devices are the weapons of choice of the insurgents in Iraq and Afghanistan, many of our Veterans have suffered repeated blast exposures producing mild traumatic brain injury (mTBI). Ominously, accumulating evidence suggests that repeated mTBIs can produce a very serious middle age onset brain disorder called chronic traumatic encephalopathy (CTE) that has been observed in professional football players and boxers. mTBI also increases the risk for later life Alzheimer's disease (AD). Abnormalities of a brain protein called tau are central to CTE and AD. We have demonstrated that the cholesterol-lowering drug, simvastatin, may also normalize brain tau. In this study, we will treat Iraq and Afghanistan Veterans with simvastatin to demonstrate feasibility of using this drug to reduce risk for CTE and AD.